| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Human immunodeficiency virus type 1 (HIV-1) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Human Immunodeficiency Virus type 1 (HIV-1) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10003582 |
| E.1.2 | Term | Asymptomatic human immunodeficiency virus type I infection |
| E.1.2 | System Organ Class | 100000004862 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To demonstrate the non-inferior antiviral activity of switching to dolutegravir (DTG) plus rilpivirine (RPV) once daily compared to continuation of current antiretroviral regimen (CAR) over 48 weeks in HIV-1 infected antiretroviral therapy (ART)-experienced subjects. |
|
| E.2.2 | Secondary objectives of the trial |
* To evaluate the immunological activity of DTG + RPV once daily compared to continuation of CAR.
* To evaluate the antiviral activity of DTG + RPV once daily compared to continuation of CAR.
* To evaluate the safety and tolerability of DTG + RPV once daily compared to continuation of CAR over time.
* To evaluate renal (in urine and blood), bone (in blood), and cardiovascular biomarkers (in blood) in subjects treated with DTG + RPV compared to continuation of CAR.
* To evaluate the effects of DTG + RPV once daily on fasting lipids over time compared to continuation of CAR.
* To assess viral resistance in subjects meeting Virologic Withdrawal Criteria.
* To evaluate DTG and RPV trough concentrations.
* To evaluate the DTG and RPV trough concentrations over time during the initial post-switch period in the first 20 subjects who switch from EFV or NVP to DTG + RPV.
REFER TO PROTOCOL (page 18, section3) FOR COMPLETE LIST
SECONDARY OBJECTIVES. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Title: Genetic Research, 26-FEB-2015, version 01 (2014N208737_01)
The objectives of the genetic research are to investigate a relationship between genetic variants and:
- Response to medicine, including DTG + RPV or any concomitant medicines;
- HIV-1 susceptibility, severity and progression and related conditions.
Title: An evaluation of bone mineral density in HIV-1-infected adult subjects switching from a tenofovir-containing antiretroviral therapy regimen to a dolutegravir plus rilpivirine regimen
11-MAR-2015, Version 0 (2014N221875_00)
Primary Objective: To evaluate the change in BMD assessed by areal density in total hip at 48 weeks following switch of subjects from an ART regimen containing TDF to DTG + RPV once daily compared to continued therapy with the TDF-containing regimen
|
|
| E.3 | Principal inclusion criteria |
Eligible subjects must:
- be able to understand and comply with protocol requirements, instructions, and restrictions;
- be likely to complete the study as planned;
- be considered appropriate candidates for participation in an investigative clinical trial with oral medication (e.g., no active substance abuse, acute major organ disease, or planned long-term work assignments out of the country, etc.).
Subjects eligible for enrollment in the study must meet all of the following criteria:
1. HIV-1 infected men or women ≥18 years of age;
2. Must be on uninterrupted current regimen (either the initial or second cART regimen) for at least 6 months prior to Screening.
Any prior switch, defined as a change of a single drug or multiple drugs simultaneously, must have occurred due to tolerability and/or safety concerns or access to medications, or convenience/simplification.
Acceptable stable cART regimens prior to Screening include 2 NRTIs plus:
•INI (either the initial or second cART regimen)
•NNRTI (either the initial or second cART regimen)
•Boosted PI (or atazanavir [ATV] unboosted) (either the initial or second PI-based cART regimen)
3. Documented evidence of at least two plasma HIV-1 RNA measurements <50 c/mL in the 12 months prior to Screening: one within the 6 to 12 month window, and one within 6 months prior to Screening;
4. Plasma HIV-1 RNA <50 c/mL at Screening;
5. A female, may be eligible to enter and participate in the study if she:
a. is of non-child-bearing potential either defined as post-menopausal (12 months of spontaneous amenorrhea and ≥45 years of age) or physically incapable of becoming pregnant with documented tubal ligation, hysterectomy or bilateral oophorectomy or,
b. is of child-bearing potential with a negative pregnancy test at both Screening and Day 1 and agrees to use one of the following methods of contraception to avoid pregnancy:
- Complete abstinence from intercourse from 2 weeks prior to administration of study drug, throughout the study, and for at least 2 weeks after discontinuation of all study medications and completion of the Follow-up visit;
- Any intrauterine device (IUD) with published data showing that the expected failure rate is <1% per year (not all IUDs meet this criterion, see the SPM for a listing describing criteria of approved IUDs);
- Male partner sterilization with documentation of azoospermia prior to the female subject's entry into the study and this male is the sole partner for that subject; [Hatcher, 2011]. The documentation on male sterility can come from the site personnel's review of subject's medical records, medical examination, and/or semen analysis, or medical history interview provided by her or her partner.
- Approved hormonal contraception for subjects randomly assigned to DTG + RPV arm (and for subjects randomly assigned to CAR following switch to DTG + RPV at Week 52) or approved hormonal contraception t plus a barrier method for subjects assigned to CAR through Week 52 (see the SPM for a listing of examples of approved hormonal contraception); Approved hormonal contraception includes:
-Combined estrogen and progestogen oral contraceptive [Hatcher, 2011])
-Contraceptive subdermal implant
-Injectable progestogen [Hatcher, 2011]
-Contraceptive vaginal ring [Hatcher, 2011]
-Percutaneous contraceptive patches [Hatcher, 2011]
- Any other method with published data showing that the expected failure rate is <1% per year.
Any contraception method must be used consistently, in accordance with the approved product label during treatment with study drug and for at
least 2 weeks after discontinuation of study drug. and completion of the Follow-Up Visit. The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception. Periodic abstinence (e.g. calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception. Note: these contraceptive requirements do not apply to females of reproductive potential with same sex partners only, when this is their preferred and usual lifestyle.
All subjects participating in the study should be counseled on safer sexual practices including the use and benefit/risk of effective barrier methods (e.g., male condom) and on the risk of HIV transmission to an uninfected partner.
6. Subject is willing and able to understand requirements of study participation and provide signed and dated written informed consent prior to Screening.
7. For subjects enrolled in France: a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category. |
|
| E.4 | Principal exclusion criteria |
A subject will not be eligible for inclusion in this study if any of the following criteria apply:
Exclusionary Criteria prior to Screening or Day 1
1. Within 6 months prior to Screening and after confirmed suppression to <50 c/mL on current ART regimen, any plasma HIV-1 RNA measurement >=50 c/mL;
2. Within the 6 to 12 month window prior to Screening and after confirmed suppression to <50 c/mL, any plasma HIV-1 RNA measurement >200 c/mL;
3. Within the 6 to 12 month window prior to Screening and after confirmed suppression to <50 c/mL, 2 or more plasma HIV-1 RNA measurements >=50 c/mL;
4. Any drug holiday during the window between initiating first HIV ART and 6 months prior to Screening, except for brief periods (less than 1 month) where all ART was stopped due to tolerability and/or safety concerns;
5. Any switch to a second line regimen, defined as change of a single drug or multiple drugs simultaneously, due to virologic failure to therapy (defined as a confirmed plasma HIV-1 RNA measurement > or = 400 c/mL after initial suppression to <50 c/mL while on first line HIV therapy regimen);
Exclusionary medical conditions
6. Women who are pregnant, breastfeeding or plan to become pregnant or breastfeed during the study;
7. Any evidence of an active Centers for Disease Control and Prevention (CDC) Category C disease. Exceptions include cutaneous Kaposi’s sarcoma not requiring systemic therapy and historic CD4+ lymphocyte counts of <200 cells/mm3;
8. Subjects with severe hepatic impairment (Class C) as determined by Child-Pugh Classification (Appendix 2 of study Protocol, p97);
9. Unstable liver disease (as defined by the presence of any of the following: ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, or persistent jaundice), cirrhosis, known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones);
10. Evidence of Hepatitis B virus (HBV) infection based on the results of testing at screening for Hepatitis B surface antigen (HBsAg), Hepatitis B core antibody (anti-HBc), and Hepatitis B surface antibody (HBsAb) as follows:
- Subjects positive for HBsAg are excluded;
- Subjects positive for anti-HBc (negative HBsAg status) and negative for HBsAb are excluded.
NOTE: Subjects positive for anti-HBc (negative HBsAg status) and positive for HBsAb are immune to HBV and are not excluded.
11. Subjects with an anticipated need for any Hepatitis C virus (HCV) therapy during the Early Switch Phase and for interferon-based therapy for HCV throughout the entire study period;
A subject will not be eligible for inclusion in this study if any of the following criteria apply:
12. History or presence of allergy to the study drugs or their components or drugs of their class;
13. Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or resected, non-invasive cutaneous squamous cell carcinoma, or cervical intraepithelial neoplasia; other localized malignancies require agreement between the investigator and the Study medical monitor for inclusion of the subject prior to randomization;
14. Subjects who in the investigator’s judgment pose a significant suicidality risk. Subject’s history of suicidal behavior and/or suicidal ideation should be considered when evaluating for suicide risk;
15. Any pre-existing physical or mental condition which, in the opinion of the Investigator, may interfere with the subject’s ability to comply with the dosing schedule and/or protocol evaluations or which may compromise the safety of the subject;
16. Any condition which, in the opinion of the Investigator, may interfere with the absorption, distribution, metabolism or excretion of the study drugs or render the subject unable to take oral medication;
Exclusionary Treatments prior to Screening or Day 1
17. Use of medications which are associated with Torsades de Pointes. (See SPM for a list of relevant medications);
18. Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening;
19. Treatment with any of the following agents within 28 days of Screening: radiation therapy; cytotoxic chemotherapeutic agents; any immunomodulators that alter immune responses (a list of examples is provided in the SPM);
20. Exposure to an experimental drug or experimental vaccine within either 28 days, 5 half-lives of the test agent, or twice the duration of the biological effect of the test agent, whichever is longer, prior to Day 1 of this study;
**Please refer to study Protocol 201636, for continuing list of the Exclusion Criteria** |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of subjects with plasma HIV-1 RNA <50 copies per milliliter (c/mL) at Week 48 using the Snapshot algorithm for the Intent-to-treat exposed (ITT-E) population. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Change from Baseline in CD4+ lymphocyte count at Weeks 24 and 48;
Proportion of subjects with plasma HIV-1 RNA <50 c/mL at Week 24, using the Snapshot algorithm for the ITT-E Population;
Incidence and severity of adverse events (AEs) and laboratory abnormalities over 48 weeks;
Proportion of subjects who discontinue treatment due to AEs over 48 weeks;
Change from Baseline in renal, bone, and cardiovascular biomarkers at Week 48;
Change from Baseline in fasting lipids at Weeks 24 and 48;
Incidence of observed genotypic and resistance to CAR and to DTG or RPV for subjects meeting Virologic Withdrawal Criteria;
Pre-dose concentrations of DTG and RPV at Weeks 4, 24, 48, 56, 76, 100, or Withdrawal in subjects switching to DTG + RPV
Pre-dose concentrations of DTG and RPV at Weeks 2, 4 and 8 in the first 20 subjects who switch from EFV or NVP to DTG + RPV
By Baseline third agent treatment class:
Proportion of subjects with plasma HIV-1 RNA <50 c/mL at Week 48 using the Snapshot algorithm for the ITT-E Population;
Changes from Baseline in CD4+ lymphocyte counts at Week 48;
Incidence and severity of AEs and laboratory abnormalities over 48 weeks;
Proportion of subjects who discontinue treatment due to AEs over 48 weeks;
Incidence of observed genotypic and phenotypic resistance to current antiretroviral regimen and to DTG or RPV for subjects meeting Virologic Withdrawal Criteria;
Change from Baseline in fasting lipids at Weeks 24 and 48;
Between and within treatment group comparisons will be assessed on change from Baseline in pre-specified treatment symptoms (using the HIV Symptom Index) at Weeks 4, 24, 48, 56, 76, 100 and 148 (or Withdrawal from the study);
Between and within treatment group comparisons will be assessed on change from Baseline treatment satisfaction (using the HIV TSQ) at Weeks 4, 24, 48, 56, 76, 100 and 148 (or Withdrawal from the study) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Please see field E.5.2 above for timepoints. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| current antiretroviral regimen (CAR) |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 43 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Belgium |
| Canada |
| France |
| Germany |
| Italy |
| Netherlands |
| Russian Federation |
| Spain |
| Taiwan |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of the study is defined as the last subject’s last visit/Contact. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
